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Acute liver damage associated with innate immune activation in a small nonhuman primate model of Hepacivirus infection.

Acute liver damage associated with innate immune activation in a small nonhuman primate model of Hepacivirus infection.
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Manickam C, Rajakumar P, Wachtman L, Kramer JA, Martinot AJ, Varner V, Giavedoni LD, Reeves RK,


Manickam C, Rajakumar P, Wachtman L, Kramer JA, Martinot AJ, Varner V, Giavedoni LD, Reeves RK, (click to view)

Manickam C, Rajakumar P, Wachtman L, Kramer JA, Martinot AJ, Varner V, Giavedoni LD, Reeves RK,

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Journal of virology 2016 8 3() pii

Abstract

Despite its importance in shaping adaptive immune responses, viral clearance and immune-based inflammation, tissue-specific innate immunity remains poorly characterized in Hepatitis C virus (HCV) infection due to lack of access to acute tissues. In this study we evaluated the impact of natural killer (NK), myeloid (mDC) and plasmacytoid dendritic cells (pDC) on control of virus replication and virus-induced pathology caused by another more rapidly resolving Hepacivirus, GBV-B infection of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2-3 months post-infection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, NK cells, mDCs and pDCs increased up to 3-fold in the liver. Although, no obvious numerical changes occurred in peripheral innate cells, circulating NK cells exhibited increased perforin, Ki67, and surface expression of CXCR3. These data suggested increased NK cell arming and proliferation, as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed NK cell frequencies in the liver positively correlated with plasma (R= 0.698, p = 0.015) and liver viral load (R = 0.567, p = 0.057). Finally, soluble factors associated with NK and DCs including IFN-γ and RANTES were increased in acute infection and also associated with viral loads and hepatitis. Collectively, the mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis and potentially resolution of GBV-B infection, and could provide insight into similar mechanisms in HCV.

IMPORTANCE
Hepatitis C virus (HCV) infection has created a global health crisis and, despite new effective antivirals, is still a leading cause of liver disease and death worldwide. Recent evidence suggests innate immunity could be a potential therapeutic target for HCV, but may also be a correlate of increased disease. Due to a lack of access to human tissues in acute HCV infection, in this study we evaluated the role of innate immunity in a resolving Hepacivirus, GBV-B infection of common marmosets. Collectively our data suggest that NK and DC mobilization in acute Hepacivirus infection can dampen virus replication, but also regulate acute and chronic liver damage. How these two opposing effects on the host could be modulated in future therapeutic and vaccine approaches warrants further study.

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